Acute myocardial infarction (AMI) refers to a blockage of one or more of the coronary arteries. Coronary arterial occlusion due to thrombosis is the cause of most cases of AMI. This blockage restricts the blood supply to the muscle walls of the heart and is often accompanied by symptoms such as chest pain, heavy pressure in the chest, nausea, and shortness of breath, or shooting pain in the left arm. AMI is accompanied with an inflammatory reaction which induces cardiac dysfunction and scarring. Rapid restoration of blood flow to jeopardized myocardium limits necrosis and reduces mortality. There are approximately 1.5 million cases of AMI in the United States each year, resulting in more than 500,000 deaths. Many of the deaths resulting from AMI occur before the patient can reach the hospital.
Over the last two decades, AMI mortality has been reduced through therapeutic developments and advances in cardiovascular intervention. Reperfusion therapy for the treatment of AMI consists of primary angioplasty and/or administration of a thrombolytic agent. This can be accomplished mechanically, with primary balloon angioplasty or stenting, or medically, with a thrombolytic agent. Each method has its advantages and limitations (N. Engl. J Med. 346:954–955, 2002). The choice of reperfusion therapy in the individual patient will depend on the facilities available, contraindications for an individual patient, and the cost. The aim should be the earliest possible successful reperfusion with the least risk of complications and in the most cost-effective manner. The critical time is the time to reperfusion.
In primary angioplasty, a catheter affixed with an inflatable balloon is inserted into the patient's artery and guided to the site of the blockage where the balloon is inflated to effectively force open the clot and restore blood flow to the heart walls before permanent damage occurs. In thrombolytic therapy, clot-busting drugs or thrombolytics are administered soon after a heart attack. Commonly used thrombolytics include streptokinase and tissue plasminogen activators. Blood thinners, like heparin and aspirin, are also effective for some patients.
AMI leads to rapid death of myocytes and vascular structures in the supplied region of the ventricle. The loss of myocytes, arterioles, and capillaries in the infarcted area is irreversible, resulting with time in the formation of scarred tissue. Recent reports have demonstrated that implanted bone marrow cells (BMC) could differentiate into myocytes and coronary vessels ameliorating the function of the injured heart (Orlic et al., Nature (London) 410: 701–705, 2001). These same researchers showed that the mobilization of primitive BMC prior to AMI, by the administration of granulocyte colony stimulating factor (G-CSF) in combination with stem cell factor (SCF) resulted in a significant degree of tissue regeneration in the ischemic site (Orlic et al. Proc. Nat. Acad. Sci. 98:10344–10347, 2001). Their findings in a mouse model of AMI, induced by coronary artery ligation, suggested that the mobilization of primitive BMC by cytokines might offer a noninvasive therapeutic strategy for the regeneration of the myocardium lost as a result of AMI or other pathology.
Currently available treatments for AMI, such as thrombolytic therapy and percutaneous coronary interventions, require a hospital setting including the availability of a cardiac catheterization laboratory so that there is an inherent time lag between onset of AMI and the administration of therapy. Thus, there is a need to develop quick, easy, and effective treatments for AMI to reduce the damage to the heart after a coronary occlusion. Accordingly, an object of the present invention is to provide such methods for the treatment of AMI, which are discussed in further detail herein.